New findings demonstrate that sustained neutrophil activation induces cyclooxygenase II. This newly recognized pathway suggests an autocrine pathway that down-regulates neutrophil action and enables generation of aspirin-triggered iso-lipoxins. We have recently demonstrated that iso-lipoxins are potent inhibitors of pro-inflammatory signals in vivo and exert some of their action at the gene level via a LXA4-receptor. We shall test the hypothesis that sustained activation of PMN induces a switch towards an anti-inflammatory phenotype that is reflected in eicosanoid profiles and receptor expression, and that iso- lipoxins induce this phenotype at the gene level. The present proposal will focus on: i) Establishing the eicosanoid profile in PMN that express COX II and determine if these cells generate iso-lipoxins in the presence of aspirin ii) determine if COX II induction and cytokine exposure induces differential expression of inflammatory receptors in neutrophils iii) elucidate the role for LXA4-receptor in modulating expression of cytokines, receptors and biosynthetic pathways, as well as determine if LXA4-receptor pathways are intact in an in vivo phenotype of overt neutrophil activation. Results from these specific aims will elucidate endogenous biochemical pathways that promote the self resolution of inflammation and may provide novel pharmacological tools in controlling neutrophil mediated tissue injury.